Process for the Preparation of Irinotecan Hydrochloride Trihydrate

ABSTRACT

The invention relates to an improved process for the preparation of Irinotecan hydrochloride trihydrate of formula (4) of enhanced yield, purity by contacting 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride with 7-ethyl-10-hydroxy-camptothecin [IRT-3 (synthetic)] to obtain crude Irinotecan which is subsequently purified by solvent treatment, obtaining purified irinotecan which is converted into irinotecan hydrochloride trihydrate and the invention also relates to a report of the compound 1-chlorocorbonyl-4-piperidinopiperidine hydrochloride of formula (1) and its process for preparation.

TECHNICAL FIELD

The present invention relates to an improved process for the preparationof Irinotecan hydrochloride trihydrate of formula (4) from7-ethyl-10-hydroxy-camptothecin of formula (2). The invention alsorelates to a report of compound 1-chlorocarbonyl-4-piperidinopiperidinehydrochloride of formula (1), its process for preparation and use inobtaining Irinotecan hydrochloride trihydrate.

BACKGROUND AND PRIOR ART REFERENCES

Irinotecan of formula (3) and its hydrochloride trihydrate salt offormula (4) have been reported to be an antileukemic agent. In the priorart the hydrochloride salt has been obtained from semi-synthetically orsynthetically prepared irinotecan.

Documents CZ 2002 2250, WO 9631513, U.S. Pat. No. 6,121,451, U.S. Pat.No. 6,252,079, U.S. Pat. No. 6,444,820, U.S. Pat. No. 6,723,729, WO 03089413 and WO 9901456 describes the preparation of camptothecinderivatives including irinotecan.

Prior art processes describe preparation of Irinotecan hydrochloridetrihydrate from camptothecin by obtaining7-ethyl-10-hydroxy-camptothecin (3) as one of the intermediate andcontacting with 1-chlorocarbonyl-4-piperidinopiperidine base (hereinfurther referred to as IRT-4) to obtain crude Irinotecan which ispurified by column chromatography and further converted into itshydrochloride trihydrate salt.

The present invention uses 7-ethyl-10-hydroxycamptothecin [hereinfurther referred to as IRT-3 (synthetic)] as a starting material andcontacting with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride(herein further referred to as IRT-4.HCl) to obtain crude irinotecanwhich is purified by adopting a simple process of solvent treatment andconverting purified irinotecan into Irinotecan hydrochloride trihydratehaving enhanced yield and purity.

Further the process of present invention obviates the step of columnchromatography as a purification step enabling the present processeconomical and simple.

So far, 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride and itsuse to obtain Irinotecan hydrochloride trihydrate has not been cited inthe prior art. Now, the same has been used in the present inventionwhich has led to surprising results of enhanced yield of Irinotecanhydrochloride trihydrate to two folds having improved purity level.

The above objectives could not have been achieved successfully but forusing 7-ethyl-10-hydroxy-camptothecin (synthetic) and1-chlorocarbonyl-4-peperidinopiperidine hydrochloride as startingmaterial in the present invention. Thus, the use of1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in the preparationof Irinotecan hydrochloride trihydrate has led to surprising resultsestablishing the novelty and inventiveness of the present invention. Theresult has been illustrated with examples and substantiated by theresults in the present application (Reference Table I).

Also, there has been no report of the compound1-chlorocarbonyl-4-peperidinopiperidine hydrochloride of formula (1) andits process of preparation in the prior art.

Further, the use of 1-chlorocarbonyl-4-peperidinoopiperidinehydrochloride having enhanced storage stability enables the process ofpresent invention more consistent and easily operable.

In the present application the compound coded as IRT-3 (Semi-synthetic)refers to 7-ethyl-10-hydroxy-camptothecin obtained from camptothecin ofnatural origin and IRT-3 (Synthetic) refers to7-ethyl-10-hydroxy-camptothecin available in the market.

OBJECTS OF THE INVENTION

An object of the invention is to provide1-chlorocarbonyl-4-piperidinopiperidine hydrochloride as one of thereactants for obtaining Irinotecan hydrochloride trihydrate.

Another object of the invention is to provide a process for thepreparation of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride.

Yet another objective of the invention is to provide an improved processfor the preparation of Irinotecan hydrochloride trihydrate.

Still another object of the invention is to provide a process which iseconomical and simple to perform.

Still yet another object of the invention is to provide a process whichobviates the step of column chromatography purification.

An object of the invention is to provide 1-chlorocarbonyl-4peperidopiperidine hydrochloride having enhanced storage stability.

Another object of the invention is to provide a process for preparingIrinotecan hydrochloride trihydrate with enhanced yield and purity.

SUMMARY OF THE INVENTION

The invention relates to an improved process for the preparation ofIrinotecan hydrochloride trihydrate of enhanced yield, purity bycontacting with 1-chlorocarbonyl-4-piperidinopiperidine hydrochlorideand 7-ethyl-10-hydroxy-camptothecin (synthetic) to obtain Irinotecanwhich is subsequently purified by solvent treatment and converted intoIrinotecan hydrochloride trihydrate. The present invention also relatesto a report of 1-chlorocorbonyl-4-piperidinopiperidine hydrochloride andits process for preparation

BRIEF DESCRIPTION OF FIGURES AND TABLE

FIG. 1: HPLC Chromatogram of irinotecan (IRT5) obtained as per example8.

FIG. 2: HPLC Chromatogram of irinotecan hydrochloride trihydrate(IRT.HCl.3H20) obtained as per example 8.

FIG. 3: HPLC Chromatogram of irinotecan (IRT5) obtained as per example5.

FIG. 4: HPLC Chromatogram of irinotecan hydrochloride trihydrate(IRT.HCl.3H20) obtained as per example 6.

FIG. 5: HPLC Chromatogram of irinotecan (IRT5) obtained as per example7.

FIG. 6: HPLC Chromatogram of irinotecan hydrochloride trihydrate(IRT.HCl.3H20) obtained as per example 7.

FIG. 7: HPLC Chromatogram of irinotecan (IRT5) obtained as per example9.

FIG. 8: HPLC Chromatogram of irinotecan hydrochloride trihydrate(IRT.HCl.3H20) obtained as per example 9.

Table-1: Yield and % purity of irinotecan and irinotecan hydrochloridetrihydrate obtained in examples 5 to 9.

DETAILED DESCRIPTION OF THE INVENTION

In accordance, the present invention relates to an improved process forthe preparation of Irinotecan hydrochloride trihydrate, the said processcomprising steps of:

-   -   a) dissolving by stirring 7-ethyl-10-hydroxycamptothecin in        pyridine at room temperature,    -   b) adding the solution of        1-chlorocarbonyl-4-peperidinopiperidine hydrochloride in        pyridine to step (a) solution at room temperature, continued        stirring the mixture for a period of 6 hours to 10 hours;    -   c) removing pyridine from step (b) mixture by distilling at a        temperature below 60° C., preferably below 45° C. under reduced        pressure to obtain a residue, cooling the residue to room        temperature;    -   d) dissolving the residue of step (c) in aliphatic halogenated        hydrocarbon solvent;    -   e) washing the solution of step (d) with an aqueous sodium        bicarbonate followed by DM water three times,    -   f) separating the organic layer of step (e), distilling the        organic solvent under reduced pressure to obtain an oily        residue,    -   g) cooling the oily residue of step (f) to room temperature,        adding alkane solvent stirring at room temperature to obtain a        precipitate;    -   h) separating the precipitate of step (g), washing with alkane        solvent, drying under reduced pressure at temperature ranging        between 40° C.-50° C. preferably 45° C. to obtain crude        irinotecan,    -   i) treating the crude irinotecan of step (h) with a mixture of        dimithylformamide and alcohol for 8 hours to 14 hours filtering        to obtain a residue of pure irinotecan;    -   j) preparing aqueous hydrochloric acid, adding residue of step        (i), stirring for a period of 1 hour to 2 hours to obtain a        solution;    -   k) charging carbon to step (j) solution, stirring for further 30        minutes, filter, collecting the filtrate, washing the filtrate        with chloroform;    -   l) removing water partially from the washed filtrate of step (k)        at a temperature ranging between 40° C. to 60° C. preferably        below 45° C. under vacuum,    -   m) cooling the concentrated solution of step (I) to room        temperature, then to 0° to 5° C. for a period of 2 hours to 14        hours, crystallizing Irinotecan hydrochloride trihydrate and    -   n) separating the product of step (m) and drying at a        temperature ranging between 40° to 50° C. preferably below        45° C. under reduced pressure to obtain Irinotecan hydrochloride        trihydrate of formula (4).        The present process is depicted by the scheme as shown in next        page

An embodiment of the invention provides the use of1-chlorocarbonyl-4-piperidinopiperidine hydrochloride of formula (1)which is obtained by the said process comprising steps of;

-   -   i) preparing a solution of triphosgene by dissolving under        stirring in aliphatic halogenated hydrocarbon solvent at room        temperature;    -   ii) adding solution of step (i) to a solution of        4-piperidinopiperidine in aliphatic halogenated hydrocarbon        solvent over a period of 2 hours to 6 hours at a temperature        ranging between 5° C. to 10° C.;    -   iii) stirring the mixture of step (ii) for further 2 hours to 4        hours raising the temperature up to 30° C., maintaining for 6        hours to 8 hours;    -   iv) removing aliphatic halogenated hydrocarbon solvent        completely from step (iii) mixture under vacuum at a temperature        up to below 45° C.; cooling the residue to room temperature,        adding alkane solvent, stirring, filtering the solid, drying,        and    -   v) obtaining 1-chlorocarbonyl-4-piperidinopiperidine        hydrochloride.

Another embodiment of the present invention provides the use ofaliphatic halogenated hydrocarbon solvent preferably chloroform in thework up for obtaining crude irinotecan.

Yet another embodiment of the present invention provides the use ofalkane solvent preferably n-hexane for precipitating the product crudeirinotecan.

Still another embodiment provides the use of aliphatic halogenatedhydrocarbon preferably chloroform for removing the impurities beforecrystallizing irinotecan hydrochloride trihydrate.

Sill yet another embodiment of the invention report the compound1-chlorocorbonyl-4-piperidinopiperidine hydrochloride.

Another embodiment of the invention provides a process for preparing1-chlorocarbonyl-4-piperidinopiperidine hydrochloride

Yet another embodiment of the invention provides the use of aliphatichalogenated hydrocarbon solvent preferably methylene dichloride in thepreparation of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride

Still another embodiment of the invention provides the use of alkanesolvent preferably n-hexane in the preparation of1-chlorocarbonyl-4-piperidinopiperidine hydrochloride

Still yet another embodiment of the invention provides1-chlorocarbonyl-4-piperidinopiperidine hydrochloride having enhancedstorage stability

An embodiment of the invention provides the process for obtainingirinotecan hydrochloride trihydrate having enhanced yield by two folds.

Another embodiment of the present invention provides irinotecanhydrochloride trihydrate having the purity of up 99.60% withaccompanying major known impurity up to 0.06% and major unknown impurityup to 0.09%.

Further embodiment of the invention provides a process to obtainirinotecan hydrochloride trihydrate of enhanced yield and purity.

The invention is illustrated with example and should not be construed tolimit the scope of the present invention.

EXAMPLES Example 1 Preparation of1-chlorocarbonyl-4-piperidinopiperidine Base (IRT-4)

Dissolving 4-piperidinoperidine (100 g) in benzene (1580 ml) understirring for 15 to 30 minutes at room temperature, adding a solution oftriphosgene (150 g) in benzene (660 ml) over a period of 1 to 3 hours ata temperature of 20°-25° C. Filtering the solid, washing it with benzeneand drying, then dissolve the dried solid in chloroform (5900 ml) bystirring at room temperature for about 30 minutes. Charging aqueoussodium bicarbonate solution (400 ml), stirring and separating chloroformlayer, washing the chloroform layer with water (1800 ml), separatingchloroform layer and distilling off chloroform under vacuum at atemperature up to below 45° C. to obtain1-chlorocorbonyl-4-piperidopiperidine base (60 g).

Example-2 Preparation of 1-chlorocarbonyl-4-piperidinopiperidinehydrochloride (IRT4.HCl)

Dissolving triphosgene (110 g) in dichloromethane (300 ml) with stirringfor 15 to 30 minutes at room temperature, adding a solution of4-piperidinopiperidine (100 g) in dichloromethane (300-ml) slowly over aperiod of 2 hour to 6 hours, maintaining the temperature between 5° to10° C. Stirring the mixture keeping the temperature same for furtherperiod of 2 hours to 4 hours, raising the temperature up to 30° C.,maintaining at this temperature for further period of 6 to 8 hours anddistilling the dichloromethane completely at a temperature up to below45° C. under vacuum. Cooling the residue to room temperature and addingn-hexane (200 ml), stirring filtering and drying to obtain1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (120 g)

Example-3 Preparation of 1-chlorocarbonyl-4-piperidinopiperidinehydrochloride(IRT-4.HCl)

Procedure followed is same as in Example 2 except the solvent used ischloroform.

Example-4 Preparation of 7-ethyl-10-hydroxycamptothecin (IRT-3,semi-synthetic) from Camptothecin

Step-a: Camptothecin (100 g) is taken in DM water (2000 ml), addingslowly concentrated sulfuric acid (1100 ml) at a temperature rangingbetween 45°-55° C., further maintaining the temperature around 60° C.for a period 2 hours to 4 hours, cooling the mixture to about minus 3°C., adding propionaldehyde (48 ml) and maintaining the temperaturebetween 0° to 3° C. Adding ferrous sulphate, hydrogen peroxide (130 ml),raising the temperature up to about 30° C. and maintaining for about 2hours. Charging this mixture to a solution of aqueous sodium sulphate,extracting with chloroform (3×5 l), followed by washing the chloroformlayer with water, separating chloroform layer and removing completelychloroform under vacuum up to below 45° C., obtaining a residue,treating it with dimethyl formamide (3900 ml) at a temperature rangingbetween 80°-100° C., cooling to 0° to 5° C., filtering, washing withmethanol, drying to obtain the required product of 7-ethylcamptothecin(68 g).Step-b: Charging platinum oxide (14 g) in glacial acetic acid (600 ml)flushing with hydrogen and heating to 50°-60° C. under hydrogenatmosphere around 60 psi for about 2 hours. Cooling to room temperatureand adding 7-ethylcamptothecin (70 g) in DMSO (5 ml) and hydrogenatingat a temperature of about 60° C. for a period of about 8 hours.Filtering the mixture, collecting the filtrate and adding DM water (300ml) to it under nitrogen atmosphere, adding iodobenzene diacetate (168g) in three lots at room temperature, stirring for further 3 hours,adding aqueous sodium acetate solution (1600 ml), stirring for an hour,filtering, washing to obtain wet 7-ethyl-10-hydroxycamptothecin, [280g];Step-c: Charging IRT-2 (280 g) to dimethylformaide (1400 ml) heating to90°-100° C. for a period of about 30 minutes. Cooling to 0° to 5° C.,filtering solid, washing with methanol, drying under vacuum at about60°-80° C. to obtain purified 7-ethyl-10-hydroxy camptotheticin[IRT-3(semisynthetic); 48 g].

Example-5 Preparation of Irinotecan (IRT-5)

Dissolving 7-ethyl-10-hydroxycamptothecin (50 g) obtained in example4(c) in pyridine (200 ml) under stirring at room temperature. Adding toit a solution of 1-chlorocarbonyl-4-piperidino-piperidine base (90 g) inpyridine (2000 ml) and stirring for further 6 hours to 12 hours.Distilling off pyridine completely under vacuum at a temperaturepreferably below 45° C., cool the residue to room temperature,dissolving in chloroform (2500 ml), washing the chloroform solution withan aqueous sodium bicarbonate, followed by water. Separating chloroformlayer, removing chloroform completely under vacuum, adding n-hexanefiltering, drying the solid, purifying by column chromatography toobtain purified Irinotecan (IRT-5, 30 g)

Example-6 Preparation of Irinotecan Hydrochloride Trihydrate(IRT.HCl.3H2O)

Charging IRT-5 (30 g) obtained in example 5 onto a mixture of DM water(1300 ml) and concentrated hydrochloride acid (28 ml), stirring for 1 to4 hour to dissolve completely, washing the solution thus obtained withchloroform, collecting aqueous solution. Treating the aqueous solutionwith carbon under stirring, filtering, collecting filtrate anddistilling partially water from washed filtrate under vacuum at atemperature below 45° C., cooling to 0° to 5° C. for a period of 10hours to 12 hours, filter the solid obtained, drying under vacuum below45° C. to obtain Irinotecan hydrochloride trihydrate (22.5 g).

Example-7

7-ethyl-10-hydroxycampothecin (semi-synthetic) obtained in example 4 (c)and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (90 g) areused as reactants. Following the procedure described in examples (5) and(6) irinotecan (32 g) and irinotecan hydrochloride trihydrate (30 g)respectively are obtained.

Example-8

7-ethyl-10-hydroxycamptothecin [50 g; IRT-3(synthetic)] and1-chlorocarbonyl-4-piperidinopiperidine (90 g) are used as reactants.Following the procedure of example (5) and obtaining crude irinotecan,purifying crude irinotecan by treatment with dimethyl formamide-alcoholmixture to obtain pure irinotecan (34 g). Irinotecan hydrochloridetrihydrate (25 g) is prepared as per example (6) above.

Example-9

7-ethyl-10-hydroxy camptothecin (50 g; synthetic) and1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (90 g) are used asreactants. By following the procedure of examples (8) and (6) irinotecan(80 g) and irinotecan hydrochloride trihydrate (60 g) are obtainedrespectively.

Main Advantages of the Invention;

-   1) Provides enhanced yield of Irinotecan hydrochloride trihydrate.-   2) Provides enhanced purity of Irinotecon hydrochloride trihydrate.-   3) Provides the use of one of the reactant    1-chlorocarbonyl-4-piperidinopiperidine hydrochloride with enhanced    storage stability.-   4) Process is simple and economical.

TABLE 1 Yield and % purity of irinotecan and irinotecan hydrochloridetrihydrate obtained in examples 5 to 9. Major known Major Yield Impurityunknown S. No. Reference Product (g) % Purity (%) Impurity (%) 1.Example 5 Irinotecan 30.00 99.95 0.32 0.30 Example 6 Irinotecanhydrochloride 22.50 99.32 0.12 0.12 trihydrate 2 Example 7 Irinotecan32.00 99.20 0.22 0.16 Irinotecan hydrochloride 30.00 99.35 0.06 0.15trihydrate 3 Example 8 Irinotecan 34.00 99.37 0.15 0.17 Irinotecanhydrochloride 25.00 99.36 0.27 0.12 trihydrate 4. Example 9 Irinotecan50.00 99.40 0.10 0.13 Irinotecan hydrochloride 60.00 99.60 0.06 0.09trihydrateAbove results refers to yield and purity of irinotecan and irinotecanhydrochloride trihydrate from 50 grms of 7-ethyl-10-hydroxy camptothecin(semisynthetic and synthetic) respectively.

1-16. (canceled)
 17. An improved process for the preparation ofirinotecan hydrochloride trihydrate the said process comprising stepsof: a) dissolving by stirring 7-ethyl-10-hydroxycamptothecin of formula(2) in pyridine at room temperature; b) adding solution ofi-chlorocarbonyl-4-piperidinopiperidine hydrochloride of formula (1) inpyridine to step (a) solution at room temperature, continued stirringthe mixture for a period of 6 to 10 hours; c) removing pyridine fromstep (b) mixture by distilling at a temperature below 60° C., preferablybelow 45° C. under reduced pressure to obtain a residue, cooling theresidue to room temperature; d) dissolving the residue of step (c) in analiphatic halogenated hydrocarbon solvent; e) washing the solution ofstep (d) with an aqueous sodium bicarbonate, followed by DM water threetimes, f) separating the organic layer, distilling the organic layerunder reduced pressure to obtain an oily residue, g) cooling the oilyresidue of step (f) to room temperature, adding an alkane solvent,stirring at room temperature to obtain a precipitate; h) separating theprecipitate of step (g), washing with the alkane solvent, drying underreduced pressure at a temperature ranging between 40° C. to 50° C.preferably 45° C. to obtain crude irinotecan, i) treating the crudeirinotecan of step (h) with a mixture of dimithylformamide and alcoholfor 8 to 14 hours, filtering to obtain a residue of pure irinotecan offormula (3); j) preparing aqueous hydrochloric acid, adding residue ofstep (i) and stirring for a period of 1 to 2 hours to obtain a solution;k) charging carbon to step (j) solution, stirring for further 30minutes, filtering, collecting the filtrate and washing the filtratewith aliphatic halogenated hydrocarbon solvent; l) removing waterpartially from the washed filtrate of step (k) at a temperature rangingbetween 40° C. to 60° C. preferably below 45° C. under vacuum; m)cooling the concentrated solution of step (I) to room temperature, thento 0° to 5° C for a period of 2 hours to 14 hours, crystallizingIrinotecan hydrochloride trihydrate; and n) separating the product ofstep (m) and drying at a temperature ranging between 40° to 50° C.preferably below 45° C. under reduced pressure to obtain Irinotecanhydrochloride trihydrate of formula (4).
 18. A process of claim 17,wherein in step (b) i-chlorocarbonyM-piperidinopiperidine used isobtained by the said process comprising steps of; i) preparing asolution of triphosgene by dissolving under stirring in aliphatichalogenated hydrocarbon solvent at room temperature; ii) adding solutionof step (i) to a solution of 4-piperidinopiperidine in aliphatichalogenated hydrocarbon solvent over a period of 2 to 6 hours at atemperature ranging between 5° C. to 10° C.; iii) stirring the mixtureof step (ii) for further 2 to 4 hours, raising the temperature up to 30°C, maintaining for 6 hours to 8 hours; iv) removing aliphatichalogenated hydrocarbon solvent completely from step (iii) mixture undervacuum at a temperature up to below 45° C.; cooling the residue to roomtemperature, adding alkane solvent, stirring, filtering the solid,drying; and v) obtaining 1-chlorocarbonyl-4-piperidinopiperidinehydrochloride.
 19. A process of claim 17, wherein in step (d) thealiphatic halogenated hydrocarbon solvent used, is selected from a groupconsisting of dichloromethane, dichloroethane and chloroform.
 20. Aprocess of claim 19, wherein the preferred solvent is chloroform.
 21. Aprocess of claim 17, wherein in step (g), the alkane solvent used, isselected from a group consisting of n-pentane, n-hexane and n-heptane.22. A process of claim 21, wherein the preferred solvent is n-hexane.23. A process of claim 17, wherein in step (k) the aliphatic halogenatedhydrocarbon solvent used is selected from a group consisting ofdichloromethane, dichloroethane and chloroform.
 24. A process of claim23, wherein the preferred solvent is chloroform.
 25. A process of claim18, wherein in step (i) the aliphatic halogenated solvent used isselected from a group consisting of carbon tetrachloride, chloroform,methylene dichloride and ethylene dichloride.
 26. A process of claim 25,wherein the preferred solvent is methylene dichloride.
 27. A process ofclaim 18, wherein in step (iv) the alkane solvent used is selected froma group consisting of n-pentane, n-hexane and n-heptane.
 28. A processof claim 17, wherein the preferred solvent used is n-hexane.